Cardiovascular Event Rates and Mortality According to Achieved Systolic and Diastolic Blood Pressure in Patients

Over the past century, cardiovascular disease (CVD) has remained the leading cause of death in the United States.1 A major and modifiable driver of CVD is hypertension. An estimated 80 million adults in the United States have hypertension, currently defined as blood pressure (BP) ≥140/90mmHg.2 Recent guidelines generally recommend a systolic BP (SBP) target and diastolic BP (DBP) target of 140 and 90 mmHg,3-7 respectively, for most patients. Of note, a higher SBP target of 150 mmHg is often recommended for older patients (recommendations range from over 60 years to over 85). To date, recommendations for lower limits of either SBP or DBP have never been provided by guideline writing groups.

The history of hypertension is a rich one. The first reports of increased incidence of CVD events associated with hypertension came from the Framingham Heart Study. In 1957 Dawber et al. reported that hypertension (defined at that time as ≥160/95 mmHg) was associated with increased incidence of atherosclerotic cardiovascular disease (ASCVD).8 This study and other observational studies led to the first BP treatment trials; the Veterans Administration Cooperative Study Group on Antihypertensive Agents and the Hypertension Detection and Follow-up Program (HDFP) study. Both trials demonstrated improved outcomes associated with treatment of DBP in individuals who had a DBP ≥90 or ≥115 mmHg.9-11 Subsequent trials focused on SBP targets, including the Australian Therapeutic Trial,12 European Working Party Trial,13 and the Systolic Hypertension in the Elderly Program (SHEP) trial.14 These demonstrated a reduction in CVD mortality in patients treated with antihypertensives compared to placebo when SBP >160 or >200 mmHg.14 The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a more contemporary study comparing antihypertensives that demonstrated the safety of treating SBP even more aggressively, targeting SBP <140.15

However, to this day, there remains questions about what a target "normal" blood pressure should be. Physiologically, at a certain lower limit of SBP, perfusion and autoregulation of vital organs may become impaired and result in worsening outcomes. In addition, lowering of DBP may impair coronary perfusion to the myocardium, which is uniquely dependent on diastolic blood flow. In a meta-analysis of 1 million individuals in prospective observational studies, the risk of CVD death increased above a SBP >115mmHg and DBP >75mmHg.16 Also of note from this meta-analysis was that there appeared to be a possible J-curve for DBP with a trend for increased ischemic heart disease events among those with DBP <70 mmHg. In addition, observational studies have repeatedly shown that a very low DBP is associated with increased coronary events.17-20 For example, Cruickshank et al. reported a relationship between low on-treatment DBP and mortality from myocardial infarction among patients with coronary artery disease (CAD) and hypertension.21

In keeping with this, trials targeting a more aggressive lowering of DBP failed to show any benefit. In the Hypertension Optimal Treatment (HOT) trial, there was no difference in outcomes between the groups who were allocated to a DBP target of <90, ≤85, or ≤80 mmHg.22 Indeed, among participants with prior ischemic heart disease enrolled in HOT, those treated to a DBP of 80 mmHg had a higher rate of myocardial infarction (8.3/1,000 patient-years) than those treated to a DBP of 85mmHg (6.8/1,000 patient-years, relative risk 1.22).19 The increased risk of myocardial infarction with reduction of DBP was not seen in patients without ischemic heart disease.19

Recent data from the Atherosclerosis Risk in Communities (ARIC) cohort advance our understanding of the DBP J curve, particularly as this relates to coronary events and myocardial damage as measured by high-sensitivity troponin. In the ARIC study by McEvoy et al., a DBP <70mmHg, compared with 80-89mmHg, was associated with increased odds of having an elevated high-sensitive troponin T.17 Among individuals with a baseline DBP of <60mmHg, coronary events and all-cause mortality were also higher over 21 years follow-up.17 These findings suggest that individuals with limitations to coronary perfusion, perhaps secondary to epicardial coronary stenosis or microvascular disease, are particularly vulnerable to low DBP.

Lending further evidence that lower BP is not always better, among diabetic adults enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, treatment to a target SBP of <120 mmHg versus <140 mmHg did not reduce major CVD events despite a BP reduction of ~14/6 mmHg.23 In the Ongoing Temisartan Alone and in Combination With Ramipril Global Endpoint (ONTARGET) Trial ACEI-inhibitors study, reduction of BP <140/90 was associated with improved CVD death but a target of <130/80 was associated with a trend towards increased risk.24 In the International Verapamil SR/Trandolapril Study (INVEST) trial, patients with diabetes had increased risk of all-cause mortality if achieved SBP was <115 compared to SBP <130.25 However, these analyses were post-hoc and conducted in nonrandomized groups, and, although extensive statistical adjustments were made, residual confounding cannot be ruled out.

In fact, contradicting the results from these post-hoc analysis, in the Systolic Blood Pressure Intervention Trial (SPRINT), individuals with high CV risk randomized to an intensive target SBP of <120 mmHg compared with the standard target of <140 mmHg had a lower rate of the primary composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. The mean SBP achieved in SPRINT was ~121mmHg in the intensive arm versus ~136 mmHg in the standard arm. The study excluded patients with diabetes given the ACCORD study findings.26 However, because SPRINT evaluated a target of 120 mmHg in the intensive treatment arm, we do not know if even lower SBP targets (e.g., <115 mmHg) could be harmful and, as such, results from SPRINT do not exclude the possibility of a J-curve phenomenon for SBP. This is an important consideration because observational data would suggest that risk of adverse outcomes increase above a SBP of >115mmHg,16 and it is unclear whether there is a nadir of the benefit of lowering SBP below 115-120 mmHg (and what the value of this nadir is), below which the risk of adverse outcomes increase. Furthermore, it is worth noting that there was no benefit for myocardial infarction in those treated to an intensive SBP target in this trial, and SPRINT did not evaluate the effect of DBP.

In this context, the recently published results from the Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease (CLARIFY) study of 22,672 patients being treated for hypertension is a noteworthy attempt to shed light on remaining areas of uncertainty in this field of scholarship.18 In CLARIFY, after a median follow-up of 5 years, 9.3% of patients met the primary composite outcome of myocardial infarction, stroke or cardiovascular death, consistent with high risk individuals. In the study, both SBP ≥140 mmHg and <120 mmHg was associated with increased risk of CV events compared with SBP of 120-129 mmHg. The mean SBP in the <120 mmHg group was 114 mmHg. Taken together with previous studies and the SPRINT findings, the CLARIFY results suggest that a target SBP around 120 mmHg is likely safe but that further reductions may lead to adverse outcomes, particularly in individuals with pre-existing restrictions to coronary blood flow (like patients with known coronary artery disease, such as those enrolled in CLARIFY).

Similarly, in the CLARIFY study a DBP ≥80 mmHg or <70 mmHg compared with 70-79 mmHg (reference) was associated with increased CVD events. In addition, patients with a DBP <60 mmHg had a risk of CV events that was two-fold higher than the reference group. These CLARIFY study findings support previous observational studies demonstrating the increased risk of CVD events with lowering DBP in individuals with CAD as discussed above. However, like many other studies, this CLARIFY analysis is post-hoc and observational in nature. Thus, further studies that would add to the DBP J-curve literature include results using DBP data from the SPRINT study, and randomized controlled trials evaluating the outcomes at DBP <70 mmHg.

There are a few limitations to consider when interpreting the study from the CLARIFY investigators. Patients with a low DBP but a high SBP (that is a large pulse pressure) may have worse outcomes.17 The difference between the mean SBP and DBP was highest among the DBP <60 mmHg and 60-69mmHg compared with the other groups, suggesting that some of the CLARIFY findings may relate to wide pulse-pressure and vascular stiffness and not purely DBP reduction from intensive BP medication treatment. Further, in the population with DBP <60 mmHg, stroke, coronary artery bypass grafting surgery, hospitalization for heart failure, and hemoglobin A1c were also worse. Although confounding variables were adjusted for, this raises the possibility that patient with a DBP <60 mmHg are overall sicker; thereby increasing the suspicion for an unmeasured confounder(s) in this analysis. As noted above, one such confounder could be vascular calcification and stiffness, which would be associated with relatively low DBP independent of therapy and also associated with adverse outcomes. Therefore, because of the immutable concerns for confounding in post-hoc or observational analyses, only data from prospective randomized trials, such as trials targeting specific DBP targets (below those achieved in HOT), can provide stronger evidence regarding the existence of the DBP J-curve.

In conclusion, the definition and characteristics of the SBP and DBP J-point curves continue to evolve. With the publication of the SPRINT study, there is evidence that high risk individuals benefit from aggressive SBP reduction to a target of 120 mmHg. However, the optimal SBP target could differ with the underlying characteristics of the patient population (as seen in ACCORD). In fact, the benefits of SBP lowering appears to be modified by patients' predicted cardiovascular risk based on prediction models,27 coronary artery calcium,28 or the presence of end-organ damage.29 That is, patients that are at highest risk appear to benefit from more aggressive SBP control, whereas lower risk individuals may not. The latter is supported by findings from the Heart Outcomes Prevention Evaluation-3 (HOPE-3) study reporting null results in a sample that is lower risk than the SPRINT study. However, we do not know if SBP targets below those achieved in SPRINT could be harmful, even among selected higher risk individuals (such as those with coronary artery disease). For example, in CLARIFY, adults with prior coronary artery disease who achieved a mean SBP of 114 mmHg appeared to have higher risk for events than the reference SBP group.18 In addition, several studies have shown that DBP <70 mmHg is associated with worse outcomes particularly among individuals who have CAD and therefore more vulnerable to reduced diastolic filling. Future post-hoc studies from randomized control trials, in addition to randomized trial designs are necessary to define the optimal SBP and DBP therapeutic targets for individual patients. In addition, significant variation in the normal distribution of blood pressure exists by race/ethnicity and gender that requires consideration during treatment.30-32 We believe that the future of blood pressure management requires a tailored approach, personalizing the treatment of SBP and DBP and targets based on individual patients' characteristics and preferences.

References

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Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Acute Heart Failure, Interventions and ACS, Interventions and Coronary Artery Disease, Hypertension

Keywords: Acute Coronary Syndrome, Antihypertensive Agents, Blood Pressure, Blood Pressure Determination, Cardiovascular Diseases, Confounding Factors (Epidemiology), Coronary Artery Bypass, Coronary Artery Disease, Coronary Stenosis, Diabetes Mellitus, Heart Failure, Hypertension, Myocardial Infarction, Myocardium, Ramipril, Risk Factors, Stroke, Troponin, Troponin T, Vascular Calcification, Vascular Stiffness, Verapamil, Primary Prevention, Secondary Prevention


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